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dc.contributor.authorWoolston, A
dc.contributor.authorKhan, K
dc.contributor.authorSpain, G
dc.contributor.authorBarber, LJ
dc.contributor.authorGriffiths, B
dc.contributor.authorGonzalez-Exposito, R
dc.contributor.authorHornsteiner, L
dc.contributor.authorPunta, M
dc.contributor.authorPatil, Y
dc.contributor.authorNewey, A
dc.contributor.authorMansukhani, S
dc.contributor.authorDavies, MN
dc.contributor.authorFurness, A
dc.contributor.authorSclafani, F
dc.contributor.authorPeckitt, C
dc.contributor.authorJiménez, M
dc.contributor.authorKouvelakis, K
dc.contributor.authorRanftl, R
dc.contributor.authorBegum, R
dc.contributor.authorRana, I
dc.contributor.authorThomas, J
dc.contributor.authorBryant, A
dc.contributor.authorQuezada, S
dc.contributor.authorWotherspoon, A
dc.contributor.authorKhan, N
dc.contributor.authorFotiadis, N
dc.contributor.authorMarafioti, T
dc.contributor.authorPowles, T
dc.contributor.authorLise, S
dc.contributor.authorCalvo, F
dc.contributor.authorGuettler, S
dc.contributor.authorvon Loga, K
dc.contributor.authorRao, S
dc.contributor.authorWatkins, D
dc.contributor.authorStarling, N
dc.contributor.authorChau, I
dc.contributor.authorSadanandam, A
dc.contributor.authorCunningham, D
dc.contributor.authorGerlinger, M
dc.date.accessioned2019-06-27T09:06:48Z
dc.date.issued2019-06-26
dc.identifier.citationCancer cell, 2019, 36 (1), pp. 35 - 50.e9
dc.identifier.issn1535-6108
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3276
dc.identifier.eissn1878-3686
dc.identifier.doi10.1016/j.ccell.2019.05.013
dc.description.abstractDespite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.
dc.formatPrint
dc.format.extent35 - 50.e9
dc.languageeng
dc.language.isoeng
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectBiopsy
dc.subjectPrognosis
dc.subjectTreatment Outcome
dc.subjectGene Expression Profiling
dc.subjectDNA Mutational Analysis
dc.subjectComputational Biology
dc.subjectImmunity
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectKaplan-Meier Estimate
dc.subjectMolecular Targeted Therapy
dc.subjectTranscriptome
dc.subjectErbB Receptors
dc.subjectBiomarkers, Tumor
dc.subjectAntineoplastic Agents, Immunological
dc.titleGenomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-05-23
rioxxterms.versionofrecord10.1016/j.ccell.2019.05.013
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer cell
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublished
pubs.volume36
pubs.embargo.termsNot known
icr.researchteamGastrointestinal Cancers Clinical Trials
icr.researchteamMedicine (RMH Smith Cunningham)
icr.researchteamSystems and Precision Cancer Medicine
icr.researchteamTranslational Oncogenomics
icr.researchteamStructural Biology of Cell Signalling
dc.contributor.icrauthorWoolston, Andrew
dc.contributor.icrauthorSpain, Georgia
dc.contributor.icrauthorPunta, Marco
dc.contributor.icrauthorNewey, Alice
dc.contributor.icrauthorFurness, Andrew
dc.contributor.icrauthorLise, Stefano
dc.contributor.icrauthorGuettler, Sebastian
dc.contributor.icrauthorGerlinger, Marco


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